Processes for producing optically active 2-thiomethyl-3-phenylpropionic acid derivative and for producing intermediate therefor

ABSTRACT

The present invention provides a process for simply producing an optically active 2-thiomethyl-3-phenylpropionic acid derivative useful as an intermediate for medicines from inexpensive raw materials. An optically active 2-hydroxymethyl-3-phenylpropionic acid ester derivative which can be relatively easily obtained by asymmetric reduction reaction with an enzyme is cyclized to an optically active P-lactone derivative which is then reacted with a sulfur compound to produce an optically active 2-thiomethyl-3-phenylpropionic acid derivative in high yield.

TECHNICAL FIELD

The present invention relates to a process for producing an opticallyactive 2-thiomethyl-3-phenylpropionic acid derivative useful as anintermediate for medicines and the like, an intermediate useful forsynthesis thereof, and a process for producing the intermediate.

BACKGROUND ART

Known processes for producing optically active2-thiomethyl-3-phenylpropionic acid derivatives are roughly divided intothe three processes including a process of resolving a racemic2-thiomethyl-3-phenylpropionic acid derivative, a method of inducing atarget compound from a non-optically active material, and a method ofinducing a target compound using an optically active compound as a rawmaterial.

An example of the process of resolving a racemic derivative is a processof converting a racemic 2-thiomethyl-3-phenylpropionic acid derivativeto a salt with an optically active amine or bonding the derivative withan optically active amino acid to form a diastereomer mixture, and thenresolving the mixture by crystallization. Examples of the amine saltinclude an ephedrine salt (Japanese Unexamined Patent ApplicationPublication No. 08-59606), an N-isopropyl alaninol salt (J. Med. Chem.,1992, 35(3), pp. 602-608), and a 1-amino-indanol salt (JapaneseUnexamined Patent Application Publication No. 11-228532). Examples ofthe amino acid bonded include alanine (PCT Japanese Translation PatentPublication No. 4-501868). Another process has been also reported, inwhich an acetyl group on a sulfur atom is stereoselectively hydrolyzedwith an enzyme (U.S. Pat. No. 5,177,006A and Biotechnol. Appl. Biochem.,1992, 16(1), pp. 34-37). However, these processes have a maximum yieldof 50% due to resolution, and are far from being practical andeconomical for industrial production.

A known example of the process of inducing from a non-optically activeraw material uses asymmetric hydrogenation reaction ofα-hydroxymethylcinnamic acid derivative or its ester. There have beenreports of examples using several asymmetric catalysts (FR2772027A1,Japanese Unexamined Patent Application Publication No. 2000-229907,Aust. J. Chem., 1998, 51(6), pp. 511-514, Enantiomer, 1998, 3(2), pp.191-195, etc.). However, any one of these examples is disadvantageous inthat the catalyst is expensive and difficult to stably obtain or has lowselectivity, and is thus impractical.

As the process of inducing from an optically active raw material, therehave been reports of a process of reacting optically active2-hydroxymethyl-3-phenylpropionic acid with a Mitsunobu reagent andpotassium tioacetate (PCT Japanese Translation Patent Publication No.11-503470) and a process of converting an optically active2-sulfonyloxy-3-phenyl-1-propanol derivative or an optically active2-hydroxymethyl-3-phenylpropionic acid derivative to an optically active2-sulfonyloxy-3-phenylpropionic acid derivative and then reacting theproduct with a sulfur compound to form a target compound (WO98/05634).However, these processes are disadvantageous in that the target compoundcannot be easily isolated and purified, and the efficiency of reactionwith the sulfur compound is insufficient, and thus have needs to beimproved for industrial production.

DISCLOSURE OF INVENTION

In consideration of the above-described situation, an object of thepresent invention is to provide a practical process capable of simplyand industrially advantageously producing an optically active2-thiomethyl-3-phenylpropionic acid derivative.

As a result of intensive research in consideration of above-describedsituation, the present inventors found a process for producing anoptically active 2-thiomethyl-3-phenylpropionic acid derivative byconverting an optically active 2-sulfonyloxymethyl-3-phenylpropionicacid derivative or an optically active 2-hydroxymethyl-3-phenylpropionicacid derivative to an optically active p-lactone derivative, and thenreacting the resulting derivative with a sulfur compound. This findingresulted in completion of the present invention.

Namely, the present invention relates to a process for producing anoptically active β-lactone derivative represented by formula (2):

(wherein * represents an asymmetric carbon atom, and R¹ represents aphenyl group which may be substituted), the process comprising cyclizingan optically active 2-sulfonyloxymethyl-3-phenylpropionic acidderivative represented by formula (1):

(wherein * and R¹ represent the same as the above, and R² represents aC₁-C₁₀ alkyl group which may be substituted or a C₆-C₂₀ aryl group whichmay be substituted) Also, the present invention relates to a process forproducing an optically active 2-thiomethyl-3-phenylpropionic acidderivative represented by formula (7)

(wherein * and R¹ represent the same as the above, and R⁵ represents aC₁-C₁₀ alkyl group which may be substituted, a C₆-C₂₀ aryl group whichmay be substituted, a C₂-C₂₀ acyl group “which may be substituted, or aC₇-C₂₀ aroyl group which may be substituted), the process comprisingreacting an optically active β-lactone derivative represented by formula(2) with a sulfur compound represented by formula (6):R⁴SR⁵   (6)(wherein R⁴ represents a hydrogen atom or an alkali metal atom, and R⁵represents the same as the above).

The present invention further relates to a process for producing anoptically active 2-thiomethyl-3-phenylpropionic acid derivativerepresented by formula (7), the process comprising cyclizing anoptically active 2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid derivative represented by formula (8):

(wherein * represents the same as the above) to form an optically activeβ-lactone derivative represented by formula (2), and then reacting theβ-lactone derivative represented by formula (2) with a sulfur compoundrepresented by formula (6).

The present invention further relates to an optically active β-lactonederivative represented by formula (10):

(wherein * represents the same as the above, and R⁶ represents asubstituted phenyl group).

The present invention further relates to an optically active2-sulfonyloxymethyl-3-phenylpropionic acid ester derivative representedby formula (11):

(wherein *, R², R³, and R⁶ represent the same as the above).

The present invention further relates to an optically active2-hydroxymethyl-3-phenylpropionic acid derivative represented by formula(12):

(wherein * and R⁶ represent the same as the above).

The present invention will be described in detail below. In thespecification, the term “optically active” means that in a compoundhaving one asymmetric carbon atom, one of two enantiomers havingasymmetric carbon atoms with different absolute configurations exists ata higher ratio.

First, raw materials used in the present invention, and productionprocesses therefor will be described.

The raw materials used in the present invention include an opticallyactive 2-sulfonyloxymethyl-3-phenylpropionic acid derivative representedby formula (1):

and an optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8):

In formulae (1) and (8), * represents an asymmetric carbon atom. Informula (1), R¹ represents a phenyl group which may be substituted.Examples of a phenyl group which may be substituted include phenyl,2,3-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,2,3-propylenedioxyphenyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, o-tolyl, m-tolyl,p-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl,o-phenoxyphenyl, m-phenoxyphenyl, p-phenoxyphenyl, o-phenylphenyl,m-phenylphenyl, p-phenylphenyl, o-chlorophenyl, m-chlorophenyl,p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl,p-cyanophenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl,o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2,6-dihydroxyphenyl, and 3,4-dihydroxyphenyl. Among these groups, phenyland 3,4-methylenedioxyphenyl are preferred.

In formula (1), R²represents a C₁-C₁₀ alkyl group which may besubstituted, or a C₆-C₂₀ aryl group which may be. substituted. Thenumber of carbon atoms is a value excluding that of a substituent. Thisis true for the description below unless otherwise specified.

Examples of the C₁-C₁₀ alkyl group which may be substituted includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, trifluoromethyl, and benzyl. Examples of the C₆-C₂₀ arylgroup which may be substituted include phenyl, p-tolyl, o-tolyl,m-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl,o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl,m-nitrophenyl, and p-nitrophenyl. Among these groups, methyl, p-tolyl,phenyl, benzyl, and trifluoromethyl are preferred for obtaining a targetcompound with high purity and low production of impurities.

The present inventors found that the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8) is a novel compound having usefulness forsynthesis of an optically active 2-thiomethyl-3-phenylpropionic acidderivative.

The optically active 2-sulfonyloxymethyl-3-phenylpropionic acidderivative represented by formula (1) can be obtained by, for example,asymmetrically reducing a corresponding racemic2-formyl-3-phenylpropionic acid ester derivative with an enzyme to forman optically active 2-hydroxymethyl-3-phenylpropionic acid esterderivative represented by formula (3) (Japanese Unexamined PatentApplication Publication No. 60-199383), sulfonylating the opticallyactive 2-hydroxymethyl-3-phenylpropionic acid ester derivative (3), andthen hydrolyzing it.

The optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8) can be obtained by hydrolyzing a compoundcontaining 3,4-methylenedioxyphenyl as R¹ of the optically active2-hydroxymethyl-3-phenylpropionic acid ester derivative (3).

A process for producing the optically active2-sulfonyloxymethyl-3-phenylpropionic acid derivative (1) from theoptically active 2-hydroxymethyl-3-phenylpropionic acid ester derivative(3) will be described below.

In the optically active 2-hydroxymethyl-3-phenylpropionic acid esterderivative represented by formula (3), * and R¹ represent the same asthe above, and R³ represents a C₁-C₁₀ alkyl group which may besubstituted, or a C₆-C₂₀ aryl group which may be substituted.

Examples of the C₁-C₁₀ alkyl group which may be substituted includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, trifluoromethyl, and benzyl. Example of the C₆-C₂₀ arylgroup which may be substituted include phenyl, p-tolyl, o-tolyl,m-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl,o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl,m-nitrophenyl, and p-nitrophenyl. Among these groups, any one of methyl,ethyl, and tert-butyl is preferred for efficiently promoting thesubsequent hydrolysis to obtain the target compound in high yield.

The optically active 2-hydroxymethyl-3-phenylpropionic acid esterderivative (3) may be sulfonylated by a general process, for example,reaction with a sulfonic-acid halide represented by formula (4) in thepresence of an appropriate base:R²SO₂X   (4)In formula (4), R² represents the same as the above, and X represents ahalogen atom. Examples of the halogen atom include an iodine atom, abromine atom, and a chlorine atom, and a chlorine atom is preferred.Although the base allowed to coexist is not particularly limited as longas it can capture the produced acid, for example, tertiary amines suchas triethylamine, diisopropylethylamine, pyridine,dimethylaminopyridine, and lutidine are preferred.

The amount of each of the sulfonic acid halide (4) and I11 base used ispreferably 1 to 5 times the moles of the optically active2-hydroxymethyl-3-phenylpropionic acid ester derivative (3) and morepreferably 1 to 2 times the moles from an economical viewpoint.

The reaction is performed in a proper solvent. Preferred examples of thesolvent include benzene, substituted benzenes such as toluene,chloroalkanes such as methylene chloride, ethers such as tetrahydrofuranand diethyl ether, and alkanes such as hexane and pentane. Among thesesolvents, toluene is more preferred.

The reaction temperature is preferably −10 to 50° C. and more preferably−5 to 30° C. The reaction may be stopped when the raw materialdisappears, but the reaction time is preferably about 1 to 10 hours.

The above-described operation can produce an optically active2-sulfonyloxymethyl-3-phenylpropionic acid ester derivative representedby formula (5):

In formula (5), *, R¹, R², and R³ represent the same as the above.

The present inventor found a novel compound containing a group otherthan an unsubstituted phenyl group as R¹ in formula (5), i.e., anoptically active 2-sulfonyloxymethyl-3-phenylpropionic acid esterderivative represented by formula (11):

(wherein *, R², and R³ represent the same as the above, and R⁶representsa phenyl group having a C₆-C₂₀ substituent), the compound havingusefulness for synthesis of an optically active2-thiomethyl-3-phenylpropionic acid derivative.

The optically active 2-sulfonyloxymethyl-3-phenylpropionic acid esterderivative (5) can be converted to the optically active2-sulfonyloxymethyl-3-phenylpropionic acid derivative (1) by hydrolysis.The hydrolysis is preferably performed under acid conditions because asulfonyloxy group is rapidly eliminated to form an unsaturated esterunder alkaline conditions. However, when a substituent on a benzene ringmay produce some reaction under the acid conditions, reaction conditionsmust be carefully determined. For example, the reaction conditions for acase in which a methylenedioxy group relatively weak against an acid ispresent on a benzene ring will be described in detail below.

As an acid, at least one acid is preferably selected from the groupconsisting of acetic acid, formic acid, hydrochloric acid, sulfuricacid, p-toluenesulfonic acid, methanesulfonic acid, andtrifluoromethanesulfonic acid, and combination of acetic acid and eithersulfuric acid or p-toluenesulfonic acid is more preferred.

Either sulfuric acid or p-toluenesulfonic acid is preferably added as anaqueous solution. The concentration of the acid is preferably 2 to 30%by weight and more preferably 5 to 20% by weight. The amount of the acidadded is preferably 0.1 to 5 times and more preferably 0.25 to 2 timesby mole based on the optically active2-sulfonyloxymethyl-3-phenylpropionic acid ester derivative (5). Withrespect to the mixing ratio to acetic acid, the amount of acetic acidused is preferably 2 to 20 times and more preferably 2 to 10 times byweight of an aqueous sulfuric acid solution or aqueous p-toluenesulfonicacid solution.

The reaction temperature is preferably in a range of 50° C. to a refluxtemperature, and more preferably a range from 60° C. to 100° C. Thereaction time is preferably about 3 to 48 hours and more preferably 3 to30 hours because an excessively long reaction time brings about adecrease in yield due to decomposition of the product.

After the reaction, post-treatment can be performed by, for example,neutralizing the added sulfuric acid or p-toluenesulfonic acid with analkali, distilling off acetic acid under reduced pressure, and thenadding water and an organic solvent to the residue for extraction. Asthe alkali, for example, an alkali metal hydroxide, an alkali metalhydrogen carbonate, and an alkali metal carbonate are preferred. Inparticular, sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium hydrogen carbonate, potassium hydrogen carbonate, potassiumcarbonate, and sodium carbonate are preferred. As the extractionsolvent, benzene, toluene, xylene, methylene chloride, chloroform,carbon tetrachloride, diethyl ether, and ethyl acetate are preferred,and toluene and ethyl acetate are more preferred.

The crude product obtained by concentrating the resultant organic layermay be supplied to a next step without purification, or may be usedafter purification by, for example, chromatography or the like.

When the benzene ring is unsubstituted or substituted only by a groupwhich may be not decomposed with an acid, the reaction can be performedby usual acid hydrolysis of esters. Examples of the acid used include,without limitation to, mineral acids such as hydrochloric acid andsulfuric acids Lewis acids such as boron trichloride, trifluoroaceticacid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, andtrifluoromethanesulfonic acid. Among these acids, hydrochloric acid,sulfuric acid, boron trichloride, trifluoroacetic acid, andp-toluenesulfonic acid are preferred.

As the reaction solvent, a mixed solvent containing an organic solventand water, acetic acid, formic acid, or the like is used. Preferably,acetic acid, formic acid, or a mixed solvent containing water and anorganic solvent miscible with water, such as dioxane, tetrahydrofuran,or an alcohol, is used. The reaction temperature is not particularlylimited as long as the reaction proceeds, but the temperature ispreferably 0° C. to a reflux temperature and more preferably about 0° C.to 100° C. The reaction may be stopped when the yield of the targetcompound is maximized, and the reaction time is not particularlylimited. However, the reaction time is preferably about 1 to 48 hours.

Next, description will be made of a process for producing the opticallyactive 2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acidderivative (8) from a compound containing 3,4-methylenedioxyphenyl as R¹of the optically active 2-hydroxymethyl-3-phenylpropionic acid esterderivative (3).

The optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8) can be easily produced by hydrolysis of the compound containing3,4-methylenedioxyphenyl as R¹ of the optically active2-hydroxymethyl-3-phenylpropionic acid ester derivative (3). Thehydrolysis process is not particularly limited, but the hydrolysis mustbe performed under alkaline conditions because the methylenedioxy groupmay be decomposed under acid conditions. Preferred examples of thealkali used include alkali metal hydroxides, alkali metal hydrogencarbonates, and alkali metal carbonates. In particular, sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium hydrogen carbonate, potassium carbonate, and sodiumcarbonate are preferred.

The reaction is performed in an aqueous solution or a mixed solventcontaining water and an organic solvent miscible with water. As theorganic solvent miscible with water, for example, methyl alcohol, ethylalcohol, isopropyl alcohol, tetrahydrofuran, dioxane, and the like arepreferred. The reaction temperature is preferably in a range of 0° C. toa reflux temperature, and more preferably in a range of 0° C. to 60° C.because an excessively high temperature may cause racemization. Thereaction is preferably stopped immediately after the disappearance ofthe raw material is confirmed. Since an excessively long time may causeracemization, the reaction is preferably performed for about 2 to 48hours and then stopped.

When the hydrolysis is performed under acid conditions, the hydrolysismay be performed by a general process. Examples of the acid usedinclude, without limitation to, mineral acids such as hydrochloric acidand sulfuric acid, Lewis acids such as boron trichloride,trifluoroacetic acid, acetic acid, p-toluenesulfonic acid,methanesulfonic acid, and trifluoromethanesulfonic acid. In particular,hydrochloric acid, sulfuric acid, boron trichloride, trifluoroaceticacid, and p-toluenesulfonic acid are preferred.

As the reaction solvent, acetic acid, formic acid, a mixed solventcontaining an organic solvent and water, or the like is used.Preferably, acetic acid, formic acid, or a mixed solvent containingwater and an organic solvent miscible with water, such as dioxane,tetrahydrofuran, or an alcohol, is used. The reaction temperature is notparticularly limited as long as the reaction proceeds, but thetemperature is preferably 0° C. to a reflux temperature and morepreferably about 0° C. to 100° C. The reaction maybe stopped when theyield of the target compound is maximized, and the reaction time is notparticularly limited. However, the reaction time is preferably about 1to 48 hours.

Next, description will be made of a process for producing the opticallyactive β-lactone derivative represented by formula (2) of the presentinvention:

(wherein * and R¹ represents the same as the above). First, a processfor cyclizing the optically active 2-sulfonyloxymethyl-3-phenylpropionicacid derivative (1) will be described.

The reaction in a mixed solvent containing water and a proper organicsolvent can produce the generally unstable β-lactone derivative (2) inhigh yield because the optically active β-lactone derivative (2)produced by cyclization reaction is present in an organic layer, andthus hydrolytic ring-opening reaction does not proceed. As the organicsolvent used, at least one solvent is preferably selected from the groupconsisting of toluene, benzene, xylene, anisole, ethyl acetate, diethylether, methylene chloride, chloroform, and carbon tetrachloride. Inparticular, toluene and ethyl acetate are preferred.

The optically active 2-sulfonyloxymethyl-3-phenylpropionic acidderivative (1) is added to the organic solvent, and then water is addedto the solution to start the reaction. In this reaction, the pH of thereaction mixture must be adjusted by adding an appropriate alkali. Thealkali used is not particularly limited as long as the pH can beadjusted. Preferred examples of the alkali include alkali metalhydroxides, alkali metal hydrogen carbonates, and alkali metalcarbonates. In particular, sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium hydrogen carbonate, potassium hydrogencarbonate, potassium carbonate, and sodium carbonate are preferred. ThepH is preferably adjusted to 4 or more with such an alkali, andparticularly preferably adjusted in a range of 4 to 12 for obtaining thetarget compound in higher yield.

With respect to the mixing ratio between the water and the organicsolvent, the volume of the organic solvent added is preferably 1 to 10times and more preferably 1 to 5 times the volume of the water. Thereaction temperature is preferably in a range of 0° C. to a refluxtemperature. An excessively low temperature may cause a low reactionrate, while an excessively high temperature may cause a reduction inyield due to decomposition of the product. Therefore, the reaction ismore preferably performed in a range of 10° C. to 50° C. The reactionmay be stopped when the yield of the target compound is maximized, butthe reaction time is preferably about 5 to 48 hours and particularlypreferably about 5 to 30 hours.

After the reaction, the target compound, the optically active β-lactonederivative (2), is present in the organic layer and can thus beseparated from the raw material only by a separation operation. Theresultant organic layer can be supplied to a next step afterconcentration without purification, but it may be used afterpurification by, for example, chromatography or the like.

Next, description will be made of a process for producing the opticallyactive β-lactone derivative (2) by cyclizing the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8).

Synthesis of the optically active β-lactone derivative (2) bycyclization reaction of the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8) is not particularly limited as long as dehydration and condensationreaction can be performed. For example, cyclization can be performed byany one of the following five processes:

1) A process of cyclizing the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8) in the presence of an azodicarboxylic acidester represented by formula (13):R⁷O₂C—N═N—Co₂R⁸   (13)and a phosphine compound represented by formula (14):R⁹ ₃P   (14)

2) A process of reacting with the sulfonic acid-halide represented byformula (4) in the presence of a base.

3) A process-using a condensing agent such as dicyclohexylcarbodiimideor the like.

4) A process using a mixed acid anhydride produced by reaction with ahalogenated ester.

5) A process using an acid chloride produced by reaction with achlorinating agent.

First, the cyclization process 1) will be described. In formula (13), R⁷and R⁸ may be the same or different and independently represent a C₁-C₁₀alkyl group which may be substituted or a C₁-C₂₀ aryl group which may besubstituted.

Examples of the C₁-C₁₀ alkyl group which may be substituted includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, trifluoromethyl, and benzyl. Examples of the C₆-C₂₀ arylgroup which may be substituted include phenyl, o-tolyl; m-tolyl,p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-nitrophenyl,m-nitrophenyl, and p-nitrophenyl. In order to obtain the target compoundin high yield, both R⁷ and R⁸ are preferably ethyl or isopropyl.

In formula (14), R⁹ represents a C₁-C₁₀ alkyl group which may besubstituted, a C₁-C₁₀ alkoxy group which may be substituted, a C₆-C₂₀aryloxy group which may be substituted, or a C₆-C₂₀ aryl group which maybe substituted.

Examples of the C₁-C₁₀ alkyl group which may be substituted includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, trifluoromethyl, and benzyl. Examples of the C₁-C₁₀ alkoxygroup which may be substituted include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,trifluoromethyloxy, and benzyloxy. Examples of the C₆-C₂₀ aryloxy groupwhich may be substituted include phenyloxy, o-tolyloxy, m-tolyloxy,p-tolyloxy, o-chlorophenyloxy, m-chlorophenyloxy, p-chlorophenyloxy,o-nitrophenyloxy, m-nitrophenyloxy, and p-nitrophenyloxy. Examples ofthe C₆-C₂₀ aryl group which may be substituted include phenyl, o-tolyl,m-tolyl, p-tolyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl,o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, o-methoxyphenyl,m-methoxyphenyl, p-methoxyphenyl, 3,4-methylenedioxyphenyl, and2,3-methylenedioxyphenyl. In order to obtain the target compound in highyield, phenyl is preferred.

Both the azodicarboxylic acid ester represented by formula (13) and thephosphine compound represented by formula (14) are preferably used inamounts of 1 to 5 times and more preferably 1 to 3 times the moles ofthe optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8).

The reaction is preferably performed at −78° C. to 30° C. and morepreferably at −78° C. to 0° C. The disappearance of the raw materials isgenerally confirmed by reaction for several hours, but the reaction timeis preferably about 2 to 24 hours. The reaction is performed in anorganic solvent, for example, benzene, a substituted benzene such astoluene, a chloroalkane such as methylene chloride, an ether, an alkane,or tetrahydrofuran, and preferably tetrahydrofuran, toluene, ormethylene chloride.

After the reaction, the insoluble matter is removed by filtration, andthe resultant filtrate is concentrated to obtain the target compound.The resulting compound can be supplied to a next step withoutpurification, but the compound may be used after purification by, forexample, chromatography or the like.

Next, the cyclization process 2) will be described. The reaction isperformed in the coexistence of the sulfonic acid halide (4) and a base.The base allowed to coexist is not particularly limited as long as itcan capture the produced acid. Preferred examples of the base includetertiary amines such as triethylamine, diisopropylethylamine, pyridine,dimethylaminopyridine, and lutidine. The amounts of the sulfonic acidhalide and base used are preferably 1 to 5 times the moles of theoptically active 2-hydroxymethyl-3-(3,4-methylenedioxyphenyl) propionicacid derivative (8), and more preferably 1 to 2 times the moles from aneconomical viewpoint.

The reaction is performed in a proper organic solvent or without asolvent. As the solvent, benzene, a substituted benzene such as toluene,a chloroalkane such as methylene chloride, an ether, an alkane, ortetrahydrofuran is preferably used, and tetrahydrofuran, toluene, ormethylene chloride is more preferably used. Without the solvent, thereaction can be conducted by adding an excess of the base to be allowedto coexist. When the solvent is not used, the base to be added in anexcess may be selected from the above-described tertiary amines, butpyridine is preferably used. The reaction temperature is preferably −10°C. to 50° C. and more preferably −5° C. to 30° C. The reaction may bestopped when the raw materials disappear, but the reaction time ispreferably about 3 to 10 hours.

In this process, the product may be a mixture containing the opticallyactive β-lactone (2) and a compound containing 3,4-methylenedioxyphenylas R¹ of the optically active 2-sulfonyloxymethyl-3-phenylpropionic acid(1). For example, the produced compound which contains3,4-methylenedioxyphenyl as R¹ of the optically active2-sulfonyloxymethyl-3-phenylpropionic acid (1) can be cyclized by theabove-described process in a mixed solvent containing an organic solventand water to finally obtain the optically active P-lactone (2) as aproduct.

After the reaction, the reaction solution may be washed with water andthen concentrated, and the residue may be supplied to a next stepwithout purification. However, the residue may be used afterpurification by, for example, chromatography or the like. When a solventmiscible with water, such as tetrahydrofuran, is used as the reactionsolvent, the solvent may be removed before water is added, and water andan appropriate organic solvent may be added to perform extraction.

Next, the above-mentioned cyclization process 3) using a condensingagent will be described. Examples of the condensing agent includedicyclohexylcarbodiimide, diisopropylcarbodiimide, andN-ethyl-N′-3-dimethylaminopropylcarbodiimide, hydrochlorides thereof,benzotriazol-1-yl-tris-(dimethylamino)phosphonium hexafluorophosphate,and diphenylphosphoryl azide. The amount of the condensing agent used ispreferably 1 to 5 times the moles of the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8), and more preferably 1 to 2 times the moles from an economicalviewpoint.

The reaction is performed in a proper organic solvent. As the solvent,benzene, a substituted benzene such as toluene, a chloroalkane such asmethylene chloride, an ether, an alkane, or tetrahydrofuran ispreferably used, and methylene chloride is more preferably used. Thereaction temperature is preferably −10° C. to 50° C. and more preferably−5° C. to 30° C. The reaction may be stopped when the raw materialsdisappear, but the reaction time is preferably about 5 to 24 hours.

After the reaction, the reaction solution may be washed with water andthen concentrated, and the residue may be supplied to a next stepwithout purification. However, the residue may be used after purity isincreased by, for example, chromatography or the like. When a solventmiscible with water, such as tetrahydrofuran, is used as the reactionsolvent, the solvent may be removed before water is added, and water andan appropriate organic solvent may be added to perform extraction. Asthe solvent used for extraction, for example, benzene, a substitutedbenzene such as toluene, a chloroalkane such as methylene chloride, anether or an alkane is preferably used, and toluene, ethyl acetate, ormethylene chloride is more preferably used.

Furthermore, the cyclization process 4) will be described. Thehalogenated ester is represented by, for example, formula (15):

(wherein X represents a halogen atom, and R¹⁰ represents a C₁-C₁₀ alkylgroup which may be substituted). As the halogen atom X, an iodine atom,a bromine atom, and-a chlorine atom are preferred, and a chlorine atomis more preferred. Examples of the C₁-C₁₀ alkyl group R¹⁰ which may besubstituted include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl. Among these groups, methyl and ethyl arepreferred.

The reaction is performed in coexistence with a base in a proper organicsolvent. As the organic solvent, benzene, a substituted benzene such astoluene, a chloroalkane such as methylene chloride, an ether, an alkane,or tetrahydrofuran is preferably used, and tetrahydrofuran or methylenechloride is more preferably used. The base allowed to coexist is notparticularly limited as long as it can capture the produced acid.Preferred examples of the base include tertiary amines such astriethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine,and lutidine. The amounts of the halogenated formic acid ester and baseused are preferably 1 to 5 times the moles of the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8), and more preferably 1 to 2 times the moles from an economicalviewpoint.

The reaction temperature is preferably in a range of −20° C. to 30° C.and more preferably in a range of −10° C. to 10° C. The reaction veryrapidly proceeds, and the disappearance of the raw materials isconfirmed several minutes after. After the reaction, an insolublesubstance such as an inorganic salt or the like can be removed byfiltration, and the resultant filtrate can be concentrated to obtain thetarget compound. The compound can be supplied to a next step withoutpurification, but it can be used after purification by, for example,chromatography or the like.

Finally, the cyclization process 5) will be described. Although thechlorinating agent reacted is not particularly limited, thionyl chlorideor the like is preferably used. The amount of the chlorinating agentused is preferably 1 to 50 times the moles of the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivative(8), and more preferably 1 to 20 times the moles from an economicalviewpoint.

The reaction is performed in a proper organic solvent. As the organicsolvent, benzene, a substituted benzene such as toluene, a chloroalkanesuch as methylene chloride, an ether, an alkane, tetrahydrofuran,dimethylformamide, or dimethylsulfoxide is preferably used, anddimethylformamide, or dimethylsulfoxide is more preferably used. Thereaction temperature is preferably 50° C. to 60° C. and more preferablyin a range of 50° C. to 40° C. The reaction may be stopped when theyield is maximized, but the reaction time is preferably about 5 to 120hours. After the reaction, the reaction solution can be concentrated,and the residue can be supplied to a next step without purification.However, the residue may be used after purity is increased by, forexample, chromatography or the like.

The present inventors found a novel compound containing a group otherthan an unsubstituted phenyl group as R¹ in formula (2), i.e., anoptically active β-lactone derivative represented by formula (10):

(wherein * represents the same as the above, and R⁶ represents asubstituted phenyl group), the novel compound having usefulness forsynthesis of optically active 2-thiomethyl-3-phenylpropionic acid.

Next, description will be made of a process of reacting the resultantoptically active β-lactone derivative (2) with a sulfur compoundrepresented by formula (6):R⁴SR⁵   (6)to produce an optically active 2-thiomethyl-3-phenylpropionic acidderivative represented by formula (7)

In formula (6), R⁴ represents a hydrogen atom or an alkali metal atom,for example, lithium, sodium, potassium, or the like. In order to obtainthe target compound in high yield, a hydrogen atom or a potassium atomis preferred.

In formulae (6) and (7), R⁵ represents a C₁-C₁₀ alkyl group which may besubstituted, a C₆-C₂₀ aryl group which may be substituted, a C₂-C₂₀ acylgroup which may be substituted, or a C₇-C₂₀ aroyl group which may besubstituted. Examples of the C₁-C₁₀ alkyl group which may be substitutedinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, trifluoromethyl, and benzyl. Examples of the C₆-C₂₀ arylgroup which may be substituted include phenyl, o-tolyl, m-tolyl,p-tolyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl,o-methoxyphenyl, m-methoxyphenyl, and p-methoxyphenyl. Examples of theC₁-C₂₀ acyl group which may be substituted include acetyl, ethyryl,propyryl, butyryl, isobutyryl, and trifluoroacetyl. Examples of theC₇-C₂₀ aroyl group which may be substituted include benzoyl, o-toluyl,m-toluyl, p-toluyl, o-anisoyl, m-anisoyl, and p-anisoyl. In order topromote the reaction in high yield, acetyl is preferred.

The amount of the sulfur compound (6) used is preferably 1 to 5equivalents and more preferably 1 to 2 equivalents relative to theoptically active β-lactone (2).

The reaction can be performed in an organic solvent or a two-phasesystem including an organic solvent and water. When the organic solventis used alone, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, oracetonitrile is preferably used. These solvents can be used alone or asa mixed solvent of two or more. When the two-phase system including theorganic solvent and water is used, ethyl acetate, toluene, acetonitrile,benzene, xylene, methylene chloride, chloroform, or the like ispreferably used as the organic solvent. In particular, ethyl acetate ortoluene is preferably used from the viewpoint of reaction yield andenvironmental consideration. The quantitative ratio between water andthe organic solvent is not particularly limited, but the amount of theorganic solvent is preferably 1 to 10 times and more preferably 1 to 5times the volume of the water.

The reaction temperature is preferably in a range of 0° C. to a refluxtemperature and more preferably in a range of 0° C. to 60° C. Since thedisappearance of the raw materials is confirmed by reaction for about 1to 5 hours, the reaction may be stopped at the disappearance.Post-treatment is performed by distilling off the organic solvent underreduced pressure, adjusting pH of the residue to acid side by adding anacid, and then performing extraction with an organic solvent. As theacid, hydrochloric acid, sulfuric acid, nitric acid, or the like ispreferably used. The pH is preferably adjusted in a range of 1 to 7 andmore preferably in a range of 1 to 4. Although any of ordinary organicsolvents can be used without limitation, toluene, ethyl acetate,methylene chloride, and the like are preferred, and toluene and ethylacetate are particularly preferred.

The reaction with the sulfur compound containing a hydrogen atom as R⁷in formula (6) may hardly proceed under the above-described reactionconditions. In this case, an alkali or an amine may be preferablyallowed to coexist.

As the alkali, an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, or the like can be used. Preferredexamples of the alkali metal hydroxide include sodium hydroxide, lithiumhydroxide, and potassium hydroxide. Preferred examples of the alkalimetal hydrogen carbonate include sodium hydrogen carbonate, potassiumhydrogen carbonate, and lithium hydrogen carbonate. Preferred examplesof the alkali metal carbonate include sodium carbonate, potassiumcarbonate, and lithium carbonate. When the reaction is performed incoexistence with the alkali, the reaction is performed in a mixedsolvent of an organic solvent and water. As the organic solvent, ethylacetate, toluene, acetonitrile, benzene, xylene, methylene chloride,chloroform, or the like is preferably used, and ethyl acetate or tolueneis particularly preferably used from the viewpoint of reaction yield andenvironmental consideration. The quantitative ratio between the waterand the organic solvent is not particularly limited, but the amount ofthe organic solvent is preferably 1 to 10 times and more preferably 1 to5 times the volume of the water.

As the amine, triethylamine, diisopropylethylamine, pyridine,dimethylaminopyridine, lutidine, or the like is preferably used. Thereaction is preferably performed in an appropriate organic solvent, suchas dimethylsulfoxide, dimethylformamide, tetrahydrofuran, oracetonitrile. These solvents can be used alone or as a mixed solvent oftwo or more.

In use of any of the amines or alkalis, the reaction temperature, thereaction time, the post-treatment, etc. can be determined without anychange in the above-described process in which the alkali or amine doesnot coexist.

INDUSTRIAL APPLICABILITY

According to the present invention, an optically active2-thiomethyl-3-phenylpropionic acid derivative useful as an intermediatefor medicines can be simply and industrially advantageously producedfrom inexpensive raw materials.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLES

The present invention will be described in further detail below withreference to examples, but the present invention is not limited to theseexamples.

Reference Example 1 Ethyl(S)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionate

Recombinant Escherichia coli HB101 (pTSBG1) Accession No. FERM BP-7119was inoculated in 50 ml of a 2×YT medium (tripeptone 1.6%, yeast extract1.0%, NaCl 0.5%, pH=7.0) sterilized in a 500-ml Sakaguchi flask,followed by shaking culture at 37° C. for 18 hours. Then, 0.5 g of ethyl2-formyl-3-(3,4-methylenedioxyphenyl)propionate, 2.5 mg of NADP, and 0.5g of glucose were added to 50 ml of the resultant culture solution,followed by stirring at 30° C. for 24 hours. After the completion ofreaction, the reaction solution was subjected to extraction with tolueneand concentration to obtain 0.49 g of a brown oily substance. As aresult of analysis of the chemical purity and optical purity of theproduct by GC (column: TC-FFAP 5 m×0.25 mm I.D. (manufactured by GLScience Co., Ltd.), carrier gas: He=30 kPa, detection: FID, columntemperature: 150° C.) and HPLC (column: Chiralcel AS (manufactured byDaicel Chemical Industries, Ltd.), mobile phase:hexane/isopropanol=98/2, flow rate: 1 mL/min, detection wavelength: 210nm, column temperature: 40° C., detection time: R isomer 16.1 minutes, Sisomer 18.3 minutes), it was confirmed that the title compound wasobtained with a chemical purity of 96.8%, and an optical purity of 43%ee.

¹H NMR (400 Hz, CDCl₃) δ: 6.73-6.56 (3H, m) , 5.93 (2H, s), 4.12-4.23(2H, q), 3.76-3.64 (2H, m), 2.95-2.69 (3H, m), 1.27 (3H, t)

Reference Example 2 Ethyl(R)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionate

Recombinant Escherichia coli HB101(pNTCRG) Accession No. FERM BP-6898was inoculated in 50 ml of a 2×YT medium (tripeptone 1.6%, yeast extract1.0%, NaCl 0.5%, pH=7.0) sterilized in a 500-ml Sakaguchi flask,followed by shaking culture at 37° C. for 18 hours. Then, 87 g of ethyl2-formyl-3-(3,4-methylenedioxyphenyl)propionate, 27.5 mg of NADP, and 89g of glucose were added to 550 ml of the resultant culture solution,followed by stirring at 30° C. for 24 hours. After the completion ofreaction, the reaction solution was subjected to extraction with tolueneand concentration to obtain 84.1 g of a brown oily substance. As aresult of analysis of the chemical purity and optical purity of theproduct by the same method as in Reference Example 2, it was confirmedthat the title compound was obtained with a chemical purity of 96.5%,and an optical purity of 96.4% ee.

Example 1 Ethyl(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate

Ethyl (S)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionate (70.62g, 279.94 mmol) which was prepared, for example, as in Reference Example1, and triethylamine (58.53 mL, 419.91 mmol) were dissolved in toluene(630 mL), and the air in a reactor was replaced with nitrogen. Theresultant solution was cooled to an inner temperature of 0° C. in an icebath. Then, methanesulfonyl chloride (32.5 mL, 419.91 mmol) was slowlyadded dropwise to the solution over about 1.5 hours with the innertemperature kept at 10° C. or less. After the completion of theaddition, the ice bath was removed, and stirring was further continuedfor 2 hours. Then, a portion of the reaction solution was extracted andanalyzed by HPLC (column: Lichrosphere, mobile phase: aqueous phosphoricacid-potassium dihydrogen phosphate solution/acetonitrile=1/1, flowrate: 1 mL/min, detection wavelength: 210 nm, column temperature: 30°C.). As a result, it was confirmed that the raw material disappeared.The reaction solution was washed with water (400 mL×2). For caution'ssake, the washings were subjected to extraction with toluene (500 mL×1),and the toluene solution was added to the washed reaction solution.Then, the solvent was distilled off under reduced pressure to obtain thetitle compound as red oil. Analysis of the oil by ¹H NMR and HPLCconfirmed that the title compound was obtained (92.04 g, purity 96.18 wt%, yield 95.70%).

¹H NMR (400 Hz, CDCl₃) δ: 6.71-6.58 (3H, m), 5.90 (2H, s), 4.33-4.26(2H, m), 4.13 (2H, m), 3.00-2.74 (4H, m), 1.21 (3H, t)

Example 2 Ethyl(R)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate

The title compound was obtained (102.09 g, purity 92.50 wt %, yield96.0%) by the same procedure as in Example 1 using ethyl(R)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionate (75.08 g,297.62 mmol) which was prepared, for example, was in Reference Example2.

¹H NMR (400 Hz, CDCl₃) δ: 6.71-6.58 (3H, m), 5.90 (2H, s), 4.33-4.26(2H, m), 4.13 (2H, m), 3.00-2.74 (4H, m), 1.21 (3H, t)

Example 3(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

Ethyl(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate(1.92 g, 5.82 mmol) and a 10 wt% aqueous sulfuric acid solution (2.85 g,2.91 mmol) were added to acetic acid (10 g), and the resultant mixturewas stirred at 90° C. Twenty hours after, the mixture was allowed tocool to room temperature, and sodium acetate (477.41 mg, 5.82 mmol) wasadded. Then, acetic acid was distilled off under reduced pressure. Whenthe total amount was decreased to about ⅓, ethyl acetate (50 mL) wasadded to the residue, and the resultant mixture was washed three timeswith water (20 mL). The washings were subjected to extraction with ethylacetate (30 mL), and the extraction solution was mixed with the ethylacetate layer previously obtained. The resultant mixture was dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure to obtain red oil. Analysis of the oil by ¹H NMRand HPLC (column: COSMOSIL 5C18-AR (Nacalai Inc.), mobile phase: aqueousphosphoric acid-potassium dihydrogen phosphate solution(pH=2)/acetonitrile=7/3, flow rate: 1 mL/min, detection wavelength: 210nm, column temperature: 40° C.) confirmed that the title compound wasobtained (1.99 g, purity 67.80 wt %, yield 76.60%).

¹H NMR (400 Hz, CDCl₃) δ: 9.50 (1H, br), 6.75-6.63 (3H, m), 5.93 (2H,s), 3.07-2.90 (5H, m), 2.85-2.81 (1H, m)

Example 4(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

Ethyl(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate(250 mg, 740.9 μmol) and a 10 wt % aqueous p-toluenesulfonic acidsolution (720.0 mg, 378.4 μmol) were added to acetic acid (2.5 g), andthe resultant mixture was stirred at 70° C. Sixty-five hours after, thetemperature was increased to 90° C., and the reaction was furtherperformed for 22 hours. The reaction solution was allowed to cool toroom temperature and then analyzed by HPLC (under the same analyticalconditions as in Example 3). As a result, it was confirmed that thetitle compound was obtained in a yield of 80.0%.

¹H NMR (400 Hz, CDCl₃) δ: 9.50 (1H, br), 6.75-6.63 (3H, m), 5.93 (2H,s), 3.07-2.90 (5H, m), 2.85-2.81 (1H, m)

Example 5(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

Ethyl(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate(250 mg, 740.9 μmol) and a 10 wt % aqueous-sulfuric acid solution (181.5mg, 185.23 μmol) were added to acetic acid (2.5 g), and the resultantmixture was stirred at 90° C. for 49 hours. Then, the reaction solutionwas allowed to cool to room temperature and analyzed by HPLC (under thesame analytical conditions as in Example 3). As a result, it wasconfirmed that the title compound was obtained in a yield of 58.0%.

¹H NMR (400 Hz, CDCl₃) δ: 9.50 (1H, br), 6.75-6.63 (3H, m), 5.93 (2H,s), 3.07-2.90 (5H, m), 2.85-2.81 (1H, m)

Example 6(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

Ethyl(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate(250 mg, 740.9 μmol) and a 10 wt % aqueous sulfuric acid solution (90.8mg, 92.62 μmol) were added to acetic acid (2.5 g), and the resultantmixture was stirred at 90° C. for 49 hours. Then, the reaction solutionwas allowed to cool to room temperature and analyzed by HPLC (under thesame analytical conditions as in Example 3). As a result, it wasconfirmed that the title compound was obtained in a yield of 50.0%.

¹H NMR (400 Hz, CDCl₃) δ: 9.50 (1H, br), 6.75-6.63 (3H, m), 5.93 (2H,s), 3.07-2.90 (5H, m), 2.85-2.81 (1H, m)

Example 7(R)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

The same procedure as in Example 3 was carried out using ethyl(R)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionate(961.8 mg, 2.91 mmol). HPLC analysis (under the same analyticalconditions as in Example 3) of the reaction solution confirmed that thetitle compound was obtained in a yield of 83%.

¹H NMR (400 Hz, CDCl₃) δ: 9.50 (1H, br), 6.75-6.63 (3H, m), 5.93 (2H,s), 3.07-2.90 (5H, m), 2.85-2.81 (1H, m)

Example 8 (S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid (3.0 g, 9.92 mmol) was dissolved in ethyl acetate (27 g), and a 30%aqueous NaOH solution (1.72 g) was added to the resultant solution toadjust the pH to 8.14. After stirring at room temperature for 22 hours,the aqueous layer was removed with a separatory funnel, and the organiclayer was washed with water. The water washing was stopped when the pHof the water was close to 6. Then, the resultant organic layer wasconcentrated under reduced pressure to obtain red oil. As a result ofanalysis of the oil by ¹H NMR and HPLC (column: COSMOSIL 5C18-AR(Nacalai Inc.), mobile phase: aqueous phosphoric acid-potassiumdihydrogen phosphate solution (pH=2) /acetonitrile=6/4, flow rate: 1mL/min, detection wavelength: 210 nm, column temperature: 40° C.), itwas confirmed that the title compound was obtained (1.92 g, yield93.8%).

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 4.35 (1H, m),4.05-3.90 (2H, m), 3.10-2.96 (2H, m)

Example 9 (S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

(S)-2-Methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid (3.0 g, 9.92 mmol) was dissolved in ethyl acetate (27 g), and a 1Maqueous NaOH solution (4.04 g) was added to the resultant solution toadjust the pH to 5.99. After stirring at 40° C. for 8 hours, thereaction solution was analyzed by HPLC (under the same analyticalconditions as in Example 8), it was confirmed that the title compoundwas obtained in a yield of 40.1%.

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 4.35 (1H, m),4.05-3.90 (2H, m), 3.10-2.96 (2H, m)

Example 10 (R)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

(R)-2-Mesyloxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid (267.13mg, 883.67 μmol) was cyclized by the same procedure as in Example 8.Analysis of the reaction solution by HPLC (under the same analyticalconditions as in Example 8) confirmed that the title compound wasobtained in a yield of 89%.

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 4.35 (1H, m),4.05-3.90 (2H, m), 3.10-2.96 (2H, m)

Example 11 (S)-2-Hydroxymethyl-3-(3,4-methylenedioxyphenyl)-propionicacid

Ethyl (S)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)-propionate(252.26 mg, 1.0 mmol), which-was prepared, for example, as in ReferenceExample 1, was dissolved in isopropyl alcohol (3 mL), and the resultantsolution was cooled to 0° C. Then, an aqueous solution (1 mL) of sodiumhydroxide (80 mg) was added to the solution, and the mixture was stirredat 0° C. for 13 hours. Then, water (10 mL) was added to the mixture, andthe resultant solution was washed with ethyl acetate (10 mL). Theaqueous layer was adjusted to a pH of 1 to 3 with conc. hydrochloricacid, followed by extraction with ethyl acetate (10 mL×2). The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a white solid. Analysisof the white solid by ¹H NMR and HPLC (under the same analyticalconditions as in Example 3) confirmed that the title compound wasobtained (231.0 mg, yield 98.80%).

¹H NMR (400 Hz, CDCl₃) δ: 6.75-6.58 (3H, m), 5.90 (2H, s), 3.80-3.61(2H, m), 3.00-2.73 (3H, m)

Example 12 (R)-2-Hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid

The tile compound was obtained (224.0 mg, yield 95.80%) 20 by the sameprocedure as in Example 11 using ethyl(R)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionate (252.26 mg,1.0 mmol), which was prepared, for example, as in Reference Example 2.

¹H NMR (400 Hz, CDCl₃) δ: 6.75-6.58 (3H, m), 5.90 (2H, s), 3.80-3.61(2H, m), 3.00-2.73 (3H, m)

Example 13 (S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

(S)-2-Hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid (250 mg,1.04 mmol) was dissolved in tetrahydrofuran (2.5 mL) in a nitrogenatmosphere, and the resultant solution was cooled to −5° C. Then,triethylamine (144.96 μL, 1.04 mmol) and ethyl chloroformate (99.35 μL,1.04 mmol) were added to the solution, followed by stirring at −5° C.Fifteen minutes after, the temperature was increased to 0° C., and thereaction was further performed for 15 minutes. Analysis of the reactionsolution by HPLC (under the same analytical conditions as in Example 8)confirmed that the title compound was obtained in a yield 68.2%.

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 4.35 (1H, m),4.05-3.90 (2H, m), 3.10-2.96 (2H, m)

Example 14 (S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

Triphenylphosphine (262.3 mg, 1.0 mmol) was dissolved in tetrahydrofuran(4 mL) in a nitrogen atmosphere, and the resultant solution was cooledto −78° C. Then, a tetrahydrofuran (4 mL) solution of isopropylazodicarboxylate (202.2 mg, 1.0 mmol) was added dropwise to the solutionover about 10 minutes. After the completion of the addition, the mixturewas further stirred for 10 minutes, and a tetrahydrofuran (4 mL)solution of (S)-2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid (224.0 mg, 1.0 mmol) was added dropwise to the mixture over about10 minutes. After the completion of the addition, stirring was performedfor 20 minutes and then further performed for 3 hours after thetemperature was returned to room temperature. Analysis of the reactionsolution by HPLC (under the same analytical conditions as in Example 8)confirmed that the title compound was obtained in a yield 72.2%.

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 4.35 (1H, m),4.05-3.90 (2H, m), 3.10-2.96 (2H, m)

Example 15 (S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone

(S)-2-Hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid (116.4mg, 1.0 mmol) wad dissolved in pyridine (1 mL) in a nitrogen atmosphere,and the resultant solution was cooled to −20° C. Then, methanesulfonylchloride (0.12 ml) was slowly added dropwise to the solution. After thecompletion of the addition, the mixture was stirred at the sametemperature for 1 hour. Analysis of the reaction solution by HPLC (underthe same analytical conditions as in Example 8) confirmed that the titlecompound was obtained in a yield 4.9%, and(S)-2-methanesulfonyloxymethyl-3-(3,4-methylenedioxyphenyl)propionicacid was produced in a yield of 23.7%.

Example 16 (S)-2-Acetylthiomethyl-3-(3,4-methylenedioxyphenyl)propionicacid

(S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone (0.80 g, 3.88 mmol) wasadded to a mixture of toluene (12 mL) and water (4 mL) in a nitrogenatmosphere, and potassium thioacetate (665.00 mg, 5.82 mmol) was addedto the resultant mixture, followed by heating to 40° C. Two hours after,the mixture was cooled to 5° C. and then adjusted to pH 1 by adding 97%sulfuric acid. The aqueous layer was removed, and the residual organiclayer was washed with water two times. Then, the organic layer wasconcentrated to obtain yellow oil. Analysis of the yellow oil by ¹H NMRand HPLC (under the same analytical conditions as in Example 8)confirmed that the title compound was obtained (937.00 mg, yield 85.5%).

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 3.22-2.79(5H, m), 2.32 (3H, s)

Example 17 (S)-2-Acetylthiomethyl-3-(3,4-methylenedioxyphenyl)propionicacid

(S)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone (0.80 g, 3.88 mmol) wasadded to a mixture of ethyl acetate (12 mL) and water (4 mL) in anitrogen atmosphere, and potassium thioacetate (665.00 mg, 5.82 mmol)was added to the resultant mixture, followed by heating to 40° C. Twohours after, the mixture was cooled to 5° C. and then adjusted to pH 1by adding 97% sulfuric acid. The aqueous layer was removed, and theresidual organic layer was washed with water two times. Then, theorganic layer was concentrated to obtain yellow oil. Analysis of theyellow oil by ¹H NMR and HPLC (column: COSMOSIL 5C18-AR (Nacalai Inc.),mobile phase: aqueous phosphoric acid-potassium dihydrogen phosphatesolution (pH=2)/acetonitrile=7/3, flow rate: 1 mL/min, detectionwavelength: 210 nm, column temperature: 40° C.) confirmed that the titlecompound was obtained (927.00 mg, yield 84.6%).

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 3.22-2.79(5H, m), 2.32 (3H, s)

Example 18 (R)-2-Acetylthiomethyl-3-(3,4-methylenedioxyphenyl)propionicacid

(R)-3-(3,4-Methylenedioxybenzyl)-2-oxetanone (240 mg, 1.16 mmol) wasreacted by the same procedure as in Example 16. Analysis of the reactionsolution by HPLC (under the same analytical conditions as in Example 8)confirmed that the title compound was obtained in a yield of 81.5%.

¹H NMR (400 Hz, CDCl₃) δ: 6.78-6.57 (3H, m), 5.90 (2H, s), 3.22-2.79(5H, m), 2.32 (3H, s)

1. A process for producing an optically active β-lactone derivativerepresented by formula (2):

(wherein * represents an asymmetric carbon atom, and R¹ represents aphenyl group which may be substituted), the process comprising cyclizingan optically active 2-sulfonyloxymethyl-3-phenylpropionic acidderivative represented by formula (1):

(wherein * and R¹ represent the same as the above, and R² represents aC₁-C₁₀ alkyl group which may be substituted or a C₆-C₂₀ aryl group whichmay be substituted).
 2. The process according to claim 1, whereincyclization reaction is performed in a mixed solvent containing waterand an organic solvent.
 3. The process according to claim 2, wherein atleast one selected from the group consisting of toluene, benzene,xylene, anisole, ethyl acetate, diethyl ether, methylene chloride,chloroform, and carbon tetrachloride is used as the organic solvent. 4.The process according to claim 1, wherein the cyclization reaction isperformed at a pH of 4 or higher.
 5. The process according to claim 1,wherein the cyclization reaction is performed in a pH range of 4 to 12.6. The process according to claim 1, wherein the optically active2-sulfonyloxymethyl-3-phenylpropionic acid derivative represented byformula (1) is obtained by hydrolyzing an optically active2-sulfonyloxymethyl-3-phenylpropionic acid ester derivative representedby formula (5):

(wherein *, R¹, and R² represent the same as the above, and R³represents a C₁-C₁₀ alkyl group which may be substituted or a C₆-C₂₀aryl group which may be substituted by a C₆-C₂₀ group), the derivativerepresented formula (5) being produced by reacting an optically active2-hydroxymethyl-3-phenylpropionic acid ester derivative represented byformula (3):

(wherein *, R¹, and R³ represent the same as the above) with a sulfonicacid halide represented by formula (4):R²SO₂X   (4) (wherein R² represents the same as the above, and Xrepresents a halogen atom).
 7. The process according to claim 6, whereinhydrolysis is performed with at least one acid selected from the groupconsisting of acetic acid, formic acid, hydrochloric acid, sulfuricacid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.
 8. The process according to claim 6, wherein hydrolysisis performed with sulfuric acid or p-toluenesulfonic acid and aceticacid.
 9. The process according to claim 6, wherein hydrolysis isperformed at a temperature in a range of 50° C. to a reflux temperature.10. The process according to claim 6, wherein R² is methyl, p-tolyl,phenyl, benzyl, or trifluoromethyl.
 11. The process according to claim6, wherein R³ is methyl, ethyl, or tert-butyl.
 12. A process forproducing an optically active 2-thiomethyl-3-phenylpropionic acidderivative represented by formula (7):

(wherein * represents an asymmetric carbon atom, R¹ represents a phenylgroup which may be substituted, and R⁵ represents a C₁-C₁₀ alkyl groupwhich may be substituted, a C₆-C₂₀ aryl group which may be substituted,a C₂-C₂₀ acyl group which may be substituted, or a C₇-C₂₀ aroyl groupwhich may be substituted), the process comprising reacting an opticallyactive β-lactone derivative represented by formula (2):

(wherein * and R¹ represent the same as the above) with a sulfurcompound represented by formula (6):R⁴SR⁵   (6) (wherein R⁴ represents a hydrogen atom or an alkali metalatom, and R⁵ represents the same as the above).
 13. The processaccording to claim 12, wherein the optically active β-lactone derivativerepresented by formula (2) is produced by the process according toclaim
 1. 14. The process according to claim 12, wherein R⁴ is a hydrogenatom or a potassium atom.
 15. The process according to claim 12, whereinR⁵ is acetyl.
 16. The process according to claim 1 or 12, wherein R¹ isany one selected from the group consisting of phenyl,2,3-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,2,3-propylenedioxyphenyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, o-tolyl, m-tolyl,p-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl,o-phenoxyphenyl, m-phenoxyphenyl, p-phenoxyphenyl, o-phenylphenyl,m-phenylphenyl, p-phenylphenyl, o-chlorophenyl, m-chlorophenyl,p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl,p-cyanophenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl,o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2,6-dihydroxyphenyl, and 3,4-dihydroxyphenyl.
 17. The process accordingto claim 1 or 12, wherein R¹ is phenyl or 3,4-methylenedioxyphenyl. 18.The process according to claim 12, wherein the optically activeβ-lactone derivative represented by formula (2) is produced by cyclizingan optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8):

(wherein * represents an asymmetric carbon atom).
 19. The processaccording to claim 18, wherein the optically active2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid derivativerepresented by formula (8) is produced by hydrolyzing an opticallyactive 2-hydroxymethyl-3-(3,4-methylenedioxyphenyl)propionic acid esterderivative represented by formula (9):

(wherein * represents an asymmetric carbon atom, and R³ represents aC₁-C₁₀ alkyl group which may be substituted, or a C₆-C₂₀ aryl groupwhich may be substituted).
 20. The process according to claim 19,wherein R³ is methyl, ethyl, or tert-butyl.
 21. The process according toclaim 1 or 12, wherein the asymmetric carbon atom has an S absoluteconfiguration.
 22. The process according to claim 1 or 12, wherein theasymmetric carbon atom has an R absolute configuration.
 23. An opticallyactive p-lactone derivative represented by formula (10):

(wherein * represents an asymmetric carbon atom, and R⁶ represents asubstituted phenyl group).
 24. The compound according to claim 23,wherein R⁶ is any one selected from the group consisting of2,3-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,2,3-propylenedioxyphenyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, o-tolyl, m-tolyl,p-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl,o-phenoxyphenyl, m-phenoxyphenyl, p-phenoxyphenyl, o-phenylphenyl,m-phenylphenyl, p-phenylphenyl, o-chlorophenyl, m-chlorophenyl,p-chlorophenyl, o-bromophenyl m-bromophenyl, p-bromophenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl,p-cyanophenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl,o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl,2,6-dihydroxyphenyl, and 3,4-dihydroxyphenyl.
 25. The compound accordingto claim 23, wherein R⁶ is 3,4-methylenedioxyphenyl.
 26. An opticallyactive 2-sulfonyloxymethyl-3-phenylpropionic acid ester derivativerepresented by formula (11):

(wherein * represents an asymmetric carbon atom, R⁶ represents asubstituted phenyl group, R² represents a C₁-C₁₀ alkyl group which maybe substituted or a C₆-C₂₀ aryl group which may be substituted, and R³represents a C₁-C₁₀ alkyl group which may be substituted or a C₆-C₂₀aryl group which may be substituted).
 27. The compound according toclaim 26, wherein R² is methyl, p-tolyl, phenyl, benzyl, ortrifluoromethyl.
 28. The compound according to claim 26, wherein R³ ismethyl, ethyl, or tert-butyl.
 29. The compound according to claim 26,wherein R⁶ is any one selected from the group consisting of3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-propylenedioxyphenyl, o-tolyl, m-tolyl, p-tolyl, 2,3-xylyl,2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl, o-chlorophenyl,m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl,p-bromophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-cyanophenyl,m-cyanophenyl, p-cyanophenyl, o-hydroxyphenyl, m-hydroxyphenyl,p-hydroxyphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl,2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,2,6-dimethoxyphenyl, and 3,4-dimethoxyphenyl.
 30. An optically active2-hydroxymethyl-3-phenylpropionic acid derivative represented by formula(12):

(wherein * represents an asymmetric carbon atom, and R⁶ represents asubstituted phenyl group).
 31. The compound according to claim 30,wherein R⁶is any one selected from the group consisting of2,3-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,2,3-propylenedioxyphenyl, 3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, 2,3-xylyl, 2,4-xylyl,2,5-xylyl, 2,6-xylyl, 3,4-xylyl, o-chlorophenyl, m-chlorophenyl,p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, o-cyanophenyl, m-cyanophenyl,p-cyanophenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl,o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, and3,4-dimethoxyphenyl.
 32. The compound according to claim 23, 26 or 30,wherein the asymmetric carbon atom has an S absolute configuration. 33.The compound according to claim 23, 26 or 30, wherein the asymmetriccarbon atom has an R absolute configuration.